Asthma Disease Management-Evidence-Based Medicine Must Be Dynamic

It seems reasonable for physicians and clinical pharmacists to protest, at least quietly, evidence-based medicine (EBM) for its potential to become cookbook medicine. At another level, EBM cannot be cookbook medicine because unlike recipes for cooking, the evidence in EBM is constantly changing. Perhaps, therein lies the critical distinction and the absolute need to view EBM as dynamic and continually changing as new evidence becomes available, is challenged, and survives scrutiny. In this issue of JMCP, Heaton et al. challenge the value of leukotriene modifiers (LM) in disease management of asthma. Based upon the 3 clinical outcomes of emergency room visits, hospitalizations for asthma, and the use of oral prednisone (�steroid burst�) to indicate exacerbation of asthma, these authors concluded that LM use was not more effective than nonuse. Worse than no improvement in these 3 clinical outcomes, LM users appeared to have more ER visits, a higher rate of hospitalization, and a higher rate of use of oral prednisone bursts. Heaton et al. calculated that LM use added $1.63 per patient per month (PPPM) in costs (in 2002 dollars) for these 3 clinical outcomes compared with LM nonusers diagnosed with asthma.

For HEDIS quality measures in asthma management, the emphasis is placed on "the use of appropriate medication for people with asthma." The actual measure is the percentage of patients with a definition of persistent asthma who receive controller medication (methylxanthine, cromolyn sodium, leukotriene modifier, nedocromil or inhaled corticosteroid) when asthma control would be better measured by the incidence of ER visits with a primary diagnosis of asthma as a ratio of total health plan membership in person-years or as a ratio of all asthmatics as defined by International Classification of Diseases, Ninth Revision (ICD-9) codes and asthma medications. 34 Asthma control has many dimensions, which include inhaler technique, adherence to prescribed regimens, patient knowledge of asthma triggers and asthma disease management, and completion of structured asthma education programs for highrisk patients. The prescription of a "controller" medication may or may not be the best asthma care for a particular patient. So, the validity of the HEDIS measure, developed in 2000 for asthma, may not measure what it purports to measure-asthma control. As for other threats to validity, the numerator of the measure (health plan members with one or more controller medications dispensed in the measurement year) does not have the same time frame as the denominator (those persons identified as "persistent" asthmatics in the year before the measurement year). Noteworthy in the HEDIS 2006 Technical Update is the instruction for health plans to "allocate the dispensing events to the appropriate year based on the date the prescription is filled," 35 presumably because some plans were measuring the date-written field on the pharmacy claim rather than the date dispensed.
Aside from these issues regarding the assessment of the numerator in the quality measure, changes appear to be necessary for measurement of the denominator. Evaluation of information from 132,414 Kaiser Permanente health program patients nationwide who were included in one or more HEDIS persistent asthma study groups between 1999 and 2002 found significant error in the identification of patients with persistent asthma. 36 Evaluation of electronic claims and pharmacy information revealed that 47.9% of these patients identified with persistent asthma actually had evidence of persistent asthma in only 1 of the 4 years of continuous insurance and pharmacy benefit coverage and only 28.2% had at least 3 consecutive years of evidence of persistent asthma. The results of this extensive study suggest that the current 1-year qualification period for identification of persistent asthma is inadequate and results in at least 30% false-positive cases.
HEDIS measures emphasize underuse of health care services and ignore overuse and misuse of services. This emphasis on the underuse of services, when corrected, increases health system costs. 37 Measuring quality is important, but we need to be mindful that (a) measurement of quality should not impede quality improvement, (b) interpretation of quality scores is far from simple or even straightforward, (c) resource dollars spent in amassing data for quality measures necessarily makes fewer resources available for delivering care, and (d) quality performance measures must undergo continuous quality improvement.

ss Asthma Disease Management-Evidence-Based Medicine Must Be Dynamic
It seems reasonable for physicians and clinical pharmacists to protest, at least quietly, evidence-based medicine (EBM) for its potential to become cookbook medicine. 38 At another level, EBM cannot be cookbook medicine because unlike recipes for cooking, the evidence in EBM is constantly changing. Perhaps, therein lies the critical distinction and the absolute need to view EBM as dynamic and continually changing as new evidence becomes available, is challenged, and survives scrutiny.
In this issue of JMCP, Heaton et al. challenge the value of leukotriene modifiers (LM) in disease management of asthma. 2 Based upon the 3 clinical outcomes of emergency room visits, hospitalizations for asthma, and the use of oral prednisone ("steroid burst") to indicate exacerbation of asthma, these authors concluded that LM use was not more effective than nonuse. Worse than no improvement in these 3 clinical outcomes, LM users appeared to have more ER visits, a higher rate of hospitalization, and a higher rate of use of oral prednisone bursts. Heaton  This is no small matter for payers. The leading LM in the United States is montelukast (Singulair), which had community pharmacy sales of $1.85 billion in 2004, placing it at rank number 14 by expenditure among all brand-name drugs. 39 The manufacturer reported that U.S. sales of montelukast increased by 10% in the third quarter of 2005 compared with the year-earlier period. 40 In the last quarter of 2005, montelukast was the number 6 drug by expenditure for a leading pharmacy benefit manager, accounting for 1.6% of total drug benefit spending among 3,010 distinct brand and generic drugs. 41 Monelukast was used by 50 times more patients than zafirlukast (Accolate), the other LM, and had a discounted allowed charge per day of about $3.00 before copayment. Some of this spending on montelukast is for allergic rhinitis-Lakomski and Chitre found that 25% of LM utilization in 2001-2002 was not for asthma. 42 Even at 75% of current spending on montelukast, the drug ranks in the top 20 drugs in the United States, second only to combination fluticasone-salmeterol (Advair, rank number 6) among the highexpenditure drugs used in treating asthma.
Heaton et al. refer to the role of montelukast in step therapy for asthma as updated by the National Asthma Education and Prevention Program (NAEPP) in 2002. 43 These 2002 asthma treatment guidelines included the recommendation of daily use of low-dose inhaled corticosteroids for mild persistent asthma as well as "low-to-medium-dose inhaled corticosteroids and

Editorial Subjects-In This Issue and in Previous Issues
either leukotriene modifier or theophylline" as one "alternative treatment" to the "preferred treatment" with low-to-mediumdose inhaled corticosteroids and long-acting beta 2 -agonists for moderate persistent asthma.
New evidence in 2005 calls these guidelines for mild persistent asthma into question. Boushey et al. found that the group of patients with mild persistent asthma randomized to no controller (inhaled corticosteroid) therapy did not have significantly poorer lung function and experienced no greater frequency of asthma exacerbation than those who received regular treatment. 44 Daily budesonide (inhaled corticosteroid) was superior to intermittent budesonide therapy and to daily zafirlukast (LM) therapy in most clinical measures, including asthma control and symptom-free days in patients with mild persistent asthma, but daily zafirlukast therapy was not superior to intermittent zafirlukast therapy in any outcome. Based on these and other findings, Boushey et al. estimated that patients with mild persistent asthma may require, on average, as little as 1 course of inhaled budesonide every 2 years or oral corticosteroids once every 8 years. This symptom-driven treatment of mild-to-moderate exacerbations is a radical departure from current guidelines for treatment of mild persistent asthma. 45 The cost savings from a change in treatment of mild persistent asthma from daily medication use to symptom-driven corticosteroid therapy could be large since up to 75% of asthma is mild disease. 46 To put the analysis performed by Heaton et al. into additional perspective, the original drug application for montelukast provides some useful information on the clinical value of the drug. For Chronic Asthma Protocol 049, there was 4.65% improvement in FEV 1 ([forced expiratory volume in 1 second]; 8.73% for montelukast vs. 4.16% for placebo) over 8 weeks of treatment with montelukast in 198 patients versus 133 patients who received placebo). 47 A more interesting finding was that the patients who received placebo experienced an average of 25.7% of days with an asthma exacerbation over the 8 weeks versus 20.5% for montelukast (P = 0.049). Headache determined to be drug related occurred more often in the montelukast group, 3.5% vs. 0.7% for placebo.
A meta-analysis of 1 pediatric and 12 adult clinical trials for the primary outcome of the number of exacerbations requiring systemic glucocorticoids found that patients treated with LMs were 60% more likely to require systemic glucocorticoid as a result of exacerbation of asthma symptoms compared with patients on monotherapy with an inhaled corticosteroid. 48 LMs were also more likely to be withdrawn as a result of inadequate asthma control (relative risk 2.5). The study concluded that 400 mcg of beclomethasone or 200 mcg of fluticasone is more effective than 10 mg per day of montelukast or 20 mg of zafirlukast twice daily.
Since montelukast is approved by the U.S. Food and Drug Administration for use in allergic rhinitis and asthma, the value of montelukast in a subset of asthma patients with allergic rhinitis is of interest. In a review of the medical literature, The Medical Letter consultants concluded in October 2005 that comparative studies with oral antihistamines and intranasal steroids are necessary, particularly since these 2 categories of therapeutic alternatives cost less than montelukast. 49 The evidence of the value of montelukast in patients with a history of both allergic rhinitis and asthma is confined to a single randomized, crossover, placebo-controlled study in 52 patients with symptoms provoked by exposure to cats. 50 Nathan et al. randomized 863 adult and adolescent patients who received combination fluticasone propionate salmeterol (FSC) to receive either blinded fluticasone propionate aqueous nasal spray (FPANS) 200 mcg per day or montelukast 10 mg per day or placebo. 51 Montelukast was found to be inferior to FPANS in control of allergic rhinitis in these patients with persistent asthma treated with FSC, and the addition of either montelukast or FPANS resulted in no additional improvements in overall asthma control compared with FSC alone. These clinical data from the RCT performed by Nathan et al. in a large sample of patients with persistent asthma appear to add support to the challenge to the economic value of montelukast brought by Heaton et al. in this issue of JMCP. The evidence continues to evolve.